Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists

ABSTRACT

The invention provides compounds of formula (I) wherein n, A, R 1 , R 2  and R 3  are as defined in the description, and the preparation thereof. The compounds of formula (I) are useful as pharmaceuticals.

[0001] The present invention relates to novel azabicyclic carbamates,their preparation, their use as pharmaceuticals and pharmaceuticalcompositions containing them.

[0002] More particularly the invention provides a compound of formula I

[0003] wherein n is 1 or 2, R₁, R₂ and R₃, independently, are hydrogenor (C₁₋₄)alkyl and A is a group of formula

[0004] wherein m is 1, 2 or 3, X is O, S, NH or CH₂ and R₄ and R₅,independently, are hydrogen, halogen, hydroxy, (C₁₋₄)alkyl,(C₁₋₄)alkoxy, (C₁₋₄)alkylthio, (C₁₋₄)alkylamino, nitro, trifluoromethylor phenyl, in free base or acid addition salt form.

[0005] Halogen denotes fluorine, bromine, chlorine or iodine.

[0006] Any alkyl, alkoxy and alkylthio groups are branched or straightchain groups. They are preferably methyl, methoxy or methylthio groups.

[0007] On account of the asymmetrical carbon atom(s) present in thecompounds of formula I and their salts, the compounds may exist inoptically active form or in form of mixtures of optical isomers, e.g. inform of racemic mixtures. All optical isomers and their mixturesincluding the racemic mixtures are part of the present invention.

[0008] In a further aspect, the invention provides a process for theproduction of the compounds of formula I and their salts, comprising thestep of reacting a compound of formula II

[0009] wherein n, R₁ and R₂ are as defined above, with a compound offormula III

[0010] wherein R₃ and A are as defined above, andN,N′-carbonyldiimidazole or di(N-succinimidyl)carbonate, and recoveringthe resulting compound of formula I in free base or acid addition saltform.

[0011] According to a preferred embodiment, in a first step the compoundof formula III is reacted with N,N′-carbonyldiimidazole, and theresulting compound is reacted with the compound of formula II.

[0012] Alternatively, the compound of formula II can be reacted with acompound of formula IV

[0013] wherein R₃ and A are as defined above.

[0014] The reactions can be effected according to conventional methods,e.g. as described in the examples.

[0015] Working up the reaction mixtures according to the above processesand purification of the compounds thus obtained may be carried out inaccordance to known procedures. Acid addition salts may be produced fromthe free bases in known manner, and vice versa.

[0016] Compounds of formula I in optically pure form can be obtainedfrom the corresponding racemates according to well-known procedures.Alternatively, optically pure starting materials can be used.

[0017] The starting materials of formula II, III and IV are known or maybe obtained from known compounds, using conventional procedures.

[0018] Compounds of formula I and their pharmaceutically acceptable acidaddition salts, hereinafter referred to as agents of the invention,exhibit valuable pharmacological properties when tested in vitro and inanimals, and are therefore useful as pharmaceuticals.

[0019] In particular, the agents of the invention are α7 nicotinicacetylcholine receptor (nAChR) agonists.

[0020] In functional assays, the agents of the invention display highaffinity at the α7 nAChR as shown in the following tests:

[0021] a) A functional assay for affinity at human α7 nAChR is carriedout with a rat pituitary cell line stably expressing the human α7 nAChR.As a read out, the calcium influx upon stimulation of the receptor isused. In this assay, agents of the invention exhibit pEC₅₀ values ofabout 5 to about 8.

[0022] b) To assess the activity of the agents of the invention on thehuman neuronal nAChR α4β2, a similar functional assay is carried outusing a human epithelial cell line stable expressing the human α4β2subtype. In this assay, agents of the invention show selectivity for theα7 nAChR subtypes.

[0023] c) To assess the activity of the compounds of the invention onthe “ganglionic subtype” and the muscle type of nicotinic receptor,similar functional assays as described under a) are carried out with ahuman epithelial cell line stably expressing the human ganglionicsubtype or a cell line endogenously expressing the human muscle type ofnicotinic receptors. In these assays, agents of the invention display noor little activity on the ganglionic and muscle type of nicotinicreceptor subtypes.

[0024] In the model of mice showing sensory gating deficit (DBA/2-mice)described by S. Leonard et al. in Schizophrenia Bulletin 22, 431-445(1996), the agents of the invention induce significant sensory gating atconcentrations of about 10 to about 40 μM.

[0025] The agents of the invention are therefore useful for thetreatment of psychotic disorders such as schizophrenia, mania,depression and anxiety, and for the treatment of neurodegenerativedisorders such as senile dementia, Alzheimer's disease and otherintellectual impairment disorders, such as attention deficithyperactivity disorders (ADHD); Parkinson's disease, Huntington'schorea, amyotrophic lateral sclerosis and multiple sclerosis. Theusefulness of α7 nAChR agonists in neurodegeneration is documented inthe literature, e.g. in Wang et al., J. biol. Chem. 275, 5626-5632(2000).

[0026] For the above-mentioned indications, the appropriate dosage willof course vary depending upon, for example, the compound employed, thehost, the mode of administration and the nature and severity of thecondition being treated. However, in general, satisfactory results inanimals are indicated to be obtained at a daily dosage of from about0.01 to about 100, preferably from about 0.1 to about 50 mg/kg animalbody weight. In larger mammals, for example humans, an indicated dailydosage is in the range from about 1 to about 500, preferably from about5 to about 300 mg of an agent of the invention convenientlyadministered, for example, in divided doses up to four times a day or insustained release form.

[0027] The agent of the invention may be administered by anyconventional route, in particular enterally, preferably orally, forexample in the form of tablets or capsules, or parenterally, for examplein the form of injectable solutions or suspensions.

[0028] The preferred compound is the stereoisomer of the(1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid 1-(2-fluorophenyl)-ethylester, the succinate of which has a melting point of 83-84° C. and whichhas an optical rotation of +14.6° (c=1; water, 20° C., 589 nm), which isthe compound of Example 61.

[0029] In accordance with the foregoing, the present invention alsoprovides an agent of the invention, for use as a pharmaceutical, e.g.for the treatment of any condition mentioned above.

[0030] The present invention furthermore provides a pharmaceuticalcomposition comprising an agent of the invention in association with atleast one pharmaceutical carrier or diluent. Such compositions may bemanufactured in conventional manner. Unit dosage forms contain, forexample, from about 0.25 to about 150, preferably from about 1 to about25 mg of a compound according to the invention.

[0031] Moreover the present invention provides the use of an agent ofthe invention, for the manufacture of a medicament for the treatment ofany condition mentioned above.

[0032] In still a further aspect the present invention provides a methodfor the treatment of any condition mentioned above, in a subject in needof such treatment, which comprises administering to such subject atherapeutically effective amount of an agent of the invention.

[0033] The following examples illustrate the invention.

EXAMPLE 1 (1-Aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid 1-phenyl-ethylester

[0034] Imidazole-1-carboxylic acid 1-phenyl-ethyl ester

[0035] To a solution of DL-1-phenylethanol 1.21 ml (10.0 mmol) in 10 mltetrahydrofurane, N,N′-carbonyldiimidazole 1.70 g (10.5 mmol) is added.The white suspension is heated up to 50° C. and stirred for 40 minutesat this temperature. The reaction mixture is cooled and evaporated. Thecrude product is purified by flash chromatography (hexane/ethyl acetate80/20) to yield the title product as colorless oil.

[0036] (1-Aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid 1-phenyl-ethyl ester

[0037] To a solution of imidazole-1-carboxylic acid 1-phenyl-ethyl ester0.50 g (2.31 mmol) in 5 ml dimethylformamide, 3-aminoquinuclidinedihydrochloride 0.46 g (2.31 mmol) and sodium carbonate 0.49 g (4.62mmol) are added. The suspension is heated up to 80° C. and stirred for18 hours at this temperature. The reaction mixture is then cooled andextracted with water and ethylacetate. The combined organic phases aredried and evaporated. The oily residue is dried, dissolved in ether andacidified with a 4 M hydrochloric acid dioxane solution. Theprecipitating crystals are filtered, washed with ether and dried to givethe title product. Mp=71-72° C. (decomposition).

EXAMPLE 2 (1-Aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid benzyl ester

[0038] 3-Aminoquinuclidine dihydrochloride 996 mg (5.0 mmol) is addedslowly to a stirred suspension of 676 mg (15.5 mmol) sodium hydride(dispersion 55%) in dimethylformamide (15 ml). Thereafter the suspensionis stirred for another 90 minutes at room temperature and thencarbobenzoxy chloride 0.72 ml (5.1 mmol) is added slowly. After anothertwo hours at room temperature, the suspension is quenched by carefullyadding water. The solvent is then evaporated at 70° C./16 mbar. Theresidue is taken up in water and ethyl acetate. The organic phase isseparated and the water phase two-times re-extracted with ethyl acetate.The combined organic phase is dried and evaporated to give the crudeoily product which is taken up in dioxane and 0.72 ml of a 4Mhydrochloric acid is added. The precipitating product is recrystallisedfrom dioxane/ether to give the hydrochloride of the title product.Mp=192-193° C.

EXAMPLE 3 (R)-(+)-(1-Aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid benzylester

[0039] Sodium hydride (dispersion 55%) 0.33 g (7.5 mmol) is washed withpetrolether and the solvent is removed by separation (decantation).Then, the sodium hydride is carefully suspended in dimethylformamide(12.5 ml). To this suspension (R)-(+)-3-aminoquinuclidinedihydrochloride 0.50 g (2.5 mmol) is added. The initially exothermicreaction is then stirred at room temperature for one hour and thencarbobenzoxy chloride 0.39 ml (2.75 mmol) is added to the reactionmixture within 15 minutes. The again initially exothermic reaction isstirred at room temperature for 90 minutes, then the mixture is pouredinto 10% brine (NaCl/water solution) and then four-times extracted withtoluene. The combined organic phases are dried and evaporated. The crudeoily residue is dissolved in dioxane (5 ml) and 0.31 ml of a 4 Mhydrochloric acid is added. The mixture is then stirred at roomtemperature till the product precipitates. The crystals are filtered,washed with dioxane and ether and dried to give the title product.Mp=228-229° C. Optical rotation +6.3° (c=0.5, water).

EXAMPLE 4 (S)-(−)-(1-Aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid benzylester

[0040] Sodium hydride (dispersion 55%) 0.33 g (7.5 mmol) is washed withpetrolether and the solvent is removed by separation (decantation).Then, the sodium hydride is carefully suspended in dimethylformamide(12.5 ml). To this suspension (S)-(−)-3-aminoquinuclidinedihydrochloride 0.50 g (2.5 mmol) is added. The initially exothermicreaction is then stirred at room temperature for one hour and thencarbobenzoxy chloride 0.39 ml (2.75 mmol) is added to the reactionmixture within 15 minutes. The again initially exothermic reaction isstirred at room temperature for 90 minutes then the mixture is pouredinto 10% brine (NaCl/water solution) and then four-times extracted withtoluene. The combined organic phases are dried and evaporated. The crudeoily residue is dissolved in dioxane (5 ml) and 0.31 ml of a 4 Mhydrochloric acid is added. The mixture is then stirred at roomtemperature till the product precipitates. The crystals are filtered,washed with dioxane and ether and dried to give the title product.Mp=221-223° C. Optical rotation −8.0° (c=0.5, water).

EXAMPLE 5 (1-Aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid 4-butyl-benzylester

[0041] Triethylamine 1.05 ml (7.5 mmol) and 0.80 gdi-(N-succinimidyl)carbonate are added to a solution of(4-butyl-phenyl)methanol 0.47 ml (2.75 mmol) in 15 ml dichloromethane.The initial suspension is stirred at room temperature for 45 minutes tobecome a clear solution. This mixture is added dropwise to a solution of3-aminoquinuclidine 0.32 g (2.5 mmol) and 0.52 ml (1.5 mmol)triethylamine in 10 ml dichloromethane. The reaction mixture issubsequently stirred for another two hours at room temperature.Afterwards the mixture is washed with 20 ml water. The organic phase isseparated, dried and evaporated. The crude product is dissolved in 5 mldichloromethane and acidified with a saturated solution of hydrochloricacid in ether. By addition of 50 ml ether a white product precipitates.The crystals are filtered, washed with ether and dried to give the titleproduct. Mp=174-175° C. decomposition).

[0042] The following compounds of formula I wherein n is 2, R₁ and R₂are hydrogen and A is a substituted phenyl group can be prepared inanalogy to Examples 1, 2 or 5. Example R₃ R₄ R₅ Mp / Optical Rotation  6H o-OMe H 89-90° C. (hydrochloride)  7 H 2-OMe 3-OMe 93-95° C.(hydrochloride)  8 H p-phenyl H 193-195° C. (hydrochloride)  9 H o-Br H203-204° C. (hydrochloride) 10 H o-NO₂ H 177-178° C. (hydrochloride) 11H p-NO₂ H 89-90° C. (hydrochloride) 12 H 2-OMe 5-Br 147-149° C.(hydrochloride) 13 H m-phenoxy H 82-83° C. (hydrochloride) 14 H o-Cl H82-83° C. (hydrochloride) 15 H 3-NO₂ 5-NO₂ 93-94° C. (hydrochloride) 16H 3-Cl 4-Cl * 17 H m-OMe H 139-140° C. (hydrochloride) 18 H 3-NO₂ 4-Me86-88° C. (hydrochloride) 19 H 3-Me 5-Me 183-184° C. (hydrochloride) 20H p-CF₃ H 143-144° C. (hydrochloride) 21 H o-Me H 174-176° C.(hydrochloride) 22 H p-Me H 194-196° C. (hydrochloride) 23 H p-isopropylH 235° C. (hydrochloride) 24 Me H H 168-170° C. (hydrochloride) 25 Me HH 71-72° C. (hydrochloride) cis/trans racemic mixture 26 Me H H 182-184°C. (hydrochloride); Stereoiso optical rotation: +32.4° mer-1 (c = 1;water 24° C., 589 nm) 27 Me H H 151-152° C. (succinate) Stercoisooptical rotation: −9.7° (c = 1; mer-2 methanol, 22° C., 589 nm) 28 Me HH optical rotation: +12.5° Stercoiso (c = 1; methanol, 20° C., 589 mer-3nm) 29 Me H H 117-119° C. (fumarate) Stereoiso optical rotation: −25.0°mer-4 (c = 1; methanol, 20° C., 589 nm) 30 H 3-OMe 5-OMe 179-180° C.(hydrochloride) 31 H 3-Me 4-NO₂ 165-167° C. (hydrochloride) 32 Me 2-Cl4-Cl 212-214° C. (hydrochloride) 33 H p-Ethyl H 208-209° C.(hydrochloride) 34 H p-Br H 190-191° C. (hydrochloride) 35 H 3-CF₃ 5-CF₃157-158° C. (hydrochloride) 36 H p-SMe H 164-166° C. (hydrochloride) 37H 2-NO₂ 5-Me 198-199° C. (hydrochloride) 38 H 3-OMe 4-OMe 221-223° C.(hydrochloride) 39 H 2-Cl 6-Cl 251-252° C. (hydrochloride) 40 H p-CO₂MeH 220-222° C. (hydrochloride) 41 Me p-tButyl H 232-233° C.(hydrochloride) 42 Ethyl H H ** 43 Me p-Cl H 132-135° C. (hydrochloride)44 Me o-Me H 219-220° C. (hydrochloride) 45 Me p-Br H 163-165° C.(hydrochloride) 46 Me 3-Cl 4-Cl 240-241° C. (hydrochloride) 47 Me p-F H219-220° C. (hydrochloride) 48 H m-Br H 186-187° C. (hydrochloride) 49 Hm-Me H 174-175° C. (hydrochloride) 50 H m-OBenzyl H 168-169° C.(hydrochloride) 51 H 2-Cl 5-Cl 205-207° C. (hydrochloride) 52 H 2-OMe5-OMe 162-163° C. (hydrochloride) 53 H 2-NO₂ 4-Cl 204-205° C.(hydrochloride) 54 Me o-Cl H 230-232° C. (hydrochloride) cis/transracemic mixture 55 Me o-Cl H 229-230° C. (hydrochloride) Stereoisooptical rotation: - 8.6° (c = 1; mer-1 water, 20° C., 589 nm) 56 Me o-ClH 255-257° C. (hydrochloride) Stereoiso optical rotation: +26.8° mer-2(c = 1; water, 22° C., 589 nm) 57 Me o-Cl H 229-230° C. (hydrochloride)Stereoiso optical rotation: +8.9° mer-3 (c = 1; water, 20° C., 589 nm)58 Me o-Cl H 257-258° C. (hydrochloride) Stereoiso optical rotation:−30.9° mer-4 (c = 1; water, 22° C., 589 nm) 59 Me o-F H 83-84° C.(succinate) Stereoiso optical rotation: +15.4° mer-1 (c = 1; water, 20°C., 589 nm) 60 Me o-F H 146-147° C. (succinate) Stereoiso opticalrotation: +2.5° mer-2 (c = 1; water, 20° C., 589 nm) 61 Me o-F H 83-84°C. (succinate) Stereoiso optical rotation: +14.6° mer-3 (c = 1; water,20° C., 589 nm) 62 Me o-F H 136-137° C. (succinate) Stereoiso opticalrotation: −4.8° (c = 1; mer4 water, 20° C., 589 nm)

EXAMPLE 63 (1-Aza-bicyclo[2.2.2]oct-3-yl)-carbamic acidbenzo[1,3]dioxol-5-ylmethyl ester

[0043] Prepared in analogy to example 1, 2 or 5.

[0044] Mp (hydrochloride)=186-187° C.

EXAMPLE 64 (1-Aza-bicyclo[2.2.2]oct-3-yl)-carbamic acidbenzo[1,3]dioxol-4-nitro-5-ylmethyl ester

[0045] Prepared in analogy to example 1, 2 or 5.

[0046] Mp (hydrochloride)=216-218° C.

EXAMPLE 65 (1-Aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid3,4,5-trimethoxy-benzyl ester

[0047] Prepared in analogy to example 1, 2 or 5.

[0048] Mp (hydrochloride)=211-212° C.

EXAMPLE 66 1-Aza-bicyclo[2.2.2]oct-3-yl)-carbamic acidbenzo[1,2,5]thiadiazol-5-ylmethyl ester

[0049] Prepared in analogy to example 1, 2 or 5.

[0050] IS: Carbonyl absorption at 1718 cm⁻¹

1. A compound of formula I

wherein n is 1 or 2, R₁, R₂ and R₃, independently, are hydrogen or(C₁₋₄)alkyl and A is a group of formula

wherein m is 1, 2 or 3, X is O, S, NH or CH₂ and R₄ and R₅,independently, are hydrogen, halogen, hydroxy, (C₁₋₄)alkyl,(C₁₋₄)alkoxy, (C₁₋₄)alkylthio, (C₁₋₄)alkylamino, nitro, trifluoromethylor phenyl, in free base or acid addition salt form.
 2. A compoundaccording to claim 1 which is the stereoisomer of the(1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid 1-(2-fluorophenyl)-ethylester, the succinate of which has a melting point of 83-84° C. and whichhas an optical rotation of +14.6° (c=1; water, 20° C., 589 nm), in freebase or acid addition salt form.
 3. A process for the preparation of acompound of formula I as defined in claim 1, or a salt thereof, whichcomprises the step of reacting a compound of formula II

wherein n, R₁ and R₂ are as defined in claim 1, with a compound offormula III

wherein R₃ and A are as defined in claim 1, and N,N′-carbonyldiimidazoleor di(N-succinimidyl)carbonate, and recovering the resulting compound offormula I in free base or acid addition salt form.
 4. A process for thepreparation of a compound of formula I as defined in claim 1, or a saltthereof, which comprises the step of reacting a compound of formula II

wherein n, R₁ and R₂ are as defined in claim 1, with a compound offormula IV

wherein R₃ and A are as defined above, and recovering the resultingcompound of formula I in free base or acid addition salt form.
 5. Acompound of claim 1 in free base or pharmaceutically acceptable acidaddition salt form, for use as a pharmaceutical.
 6. A compound of claim1 in free base or pharmaceutically acceptable acid addition salt form,for use in the treatment of psychotic and neurodegenerative disorders.7. A pharmaceutical composition comprising a compound of claim 1 in freebase or pharmaceutically acceptable acid addition salt form, inassociation with a pharmaceutical carrier or diluent.
 8. The use of acompound of claim 1 in free base or pharmaceutically acceptable acidaddition salt form, as a pharmaceutical for the treatment of psychoticand neurodegenerative disorders.
 9. The use of a compound of claim 1 infree base or pharmaceutically acceptable acid addition salt form, forthe manufacture of a medicament for the treatment of psychotic andneurodegenerative disorders.
 10. A method for the treatment of psychoticand neurodegenerative disorders, in a subject in need of such treatment,which comprises administering to such subject a therapeuticallyeffective amount of a compound of claim 1 in free base orpharmaceutically acceptable acid addition salt form.